STAP Stem Cells: Come and Gone

September 19, 2014

Last January two articles appeared in Nature announcing a new technique for making pluripotent stem cells from mouse cells. This technique is different from the methods used by Nobel Prize winners, Shinya Yamanako and John Gordon. Their methods required turning on and off certain genetic switches that control pluripotentcy, which can be a complex, time-consuming process that is still being perfected. The two Nature articles offered an alternative and ostensibly easier method by inducing cell pluripotency through stimulation in a mild acid.

These papers were touted as game-changers for stem cell research. The lead author, Haruko Obokata of Japan, was already a rising star in stem cell research. She began her work with “STAP” (stimulus-triggered acquisition of pluripotency) stem cells during her graduate work at Harvard under the guidance of Charles Vacani at Brigham and Women’s Hospital. She then became a research scientist at Japan’s prestigious RIKEN Center for Developmental Biology where her work culminated in the publication of these papers. For a summary of the research, see here for the Nature Commentary.

Unfortunately, the story was too good to be true. Several astute Nature readers spotted some discrepancies in one of the paper’s images soon after publication. Why these image issues were not spotted by Nature’s reviewers is a little unclear. However, in an interview, a Nature representative said that they do not have the resources to review every image for every paper, so they conduct a randomized check of images.[1] Other readers noticed that parts of the methods section in one of the papers was plagiarized from another paper not authored by Obokata. Nature representatives said that they put their publications through plagiarism software, and apparently, it did not catch this case.

Several labs set to work replicating the results of the STAP stem cell papers. They reported difficulties in reproducing the same results using the published procedure. Dr. Vacani published some tips to help overcome those difficulties. RIKEN, as well as Dr. Vacani’s team, assured Nature that another scientist was able to reproduce the results; however, as it turns out, the results were not independently reproduced and were not verified.[2] Other labs were unable to reproduce STAP stem cells.

Fairly quickly after these discrepancies surfaced, one of the authors retracted his authorship and RIKEN launched its own internal investigation.[3] Image analysis showed that Obokata had merged two different images into one and re-used an image from her dissertation, but changed the caption.[4]

Obokata regrets the problems in the paper, but both she and Dr. Vacani believe STAP stem cells are a real phenomenon. Even though several of the paper’s authors retracted their authorship, Obokata and Vacani maintained that the image problems do not take away from the conclusions of the paper.

Investigators conducted genetic studies on the stem cells used in the experiment. They found that the STAP cell lines do not match the mouse from which they were supposedly taken and may be embryonic cells from other mice. Some contend that STAP stem cells may have never existed.[5]

RIKEN eventually found Obokata guilty of poor data management and research misconduct and “that she sorely lacks, not only a sense of research ethics, but also integrity and humility as a scientific researcher”[4]

Even after these findings, Obokata still stands by her work, and plans to take the next five months at RIKEN under video surveillance to prove this.[6] However, given the results of the investigation, both Obokata and Dr. Vacani eventually agreed to retract the papers. Nature published a formal retraction, stating:

We apologize for the mistakes included in the Article and Letter. These multiple errors impair the credibility of the study as a whole and we are unable to say without doubt whether the STAP-SC phenomenon is real. Ongoing studies are investigating this phenomenon afresh, but given the extensive nature of the errors currently found, we consider it appropriate to retract both papers.[7]

In August, Yoshiki Sasai, renowned stem cell scientist at RIKEN and one of the co-authors on the retracted Nature papers, was found dead near his lab. He was deputy director of RIKEN’s Center for Developmental Biology. The internal investigation committee determined that while Sasai was responsible for overseeing Obokata, he was not guilty of misconduct. Tragically, in his suicide note, Sasai stated that he was worn out from the unjust media bashing. He had been in counseling since the news of the fraud broke, and was shocked when, in June, RIKEN announced that it would disband the Center for Developmental Biology.[8]

Also in August, Charles Vacani announced that he would be taking a year-long sabbatical and will be stepping down as chairman of the anesthesiology department at Brigham and Women’s Hospital. He states that it does not have to do with the retracted Nature papers.[9]

Finally, by the end of August, a team of independent researchers at RIKEN announced that in preliminary results they could not replicate the STAP methods. RIKEN will confirm these results and is allowing Obokata to continue her attempts to replicate results while under video supervision.[10]

Bioethics Issues:

Cases of scientific fraud and misconduct concern ethicists because the public entrusts expert scientists to conduct research in an objective and ethical manner. Furthermore, sloppy research could present safety problems once the technique goes to clinical trials. The two major stop-gaps to ensure scientific objectivity and integrity are oversight by both colleagues and superiors, and independent peer review of pre-published academic articles. In the case of the STAP stem cells, both of these stop-gaps failed.

On the positive side, these discrepancies were quickly reported and investigated by other scientists. While Nature’s review process may not have picked up on the problems with the research paper, including the plagiarized section in the procedure, other scientists did look at the work with a critical eye.[11] Several of the paper authors are well-known researchers in the field with prestigious academic pedigrees, but that did not keep others from questioning the images. Also these papers would have provided publicity for the field of stem cell research, which is advantageous for other scientists in the field. Rather than being blinded by the authors’ credentials and riding on the coattails of publicity, several people stepped up to address the problems.

Several media outlets have questioned Nature’s role in this. In its commentary, Nature said that its policy is to check a small portion of papers, “When figures often involve many panels, panels duplicated between figures may, in practice, be impossible for journals to police routinely without disproportionate editorial effort. By contrast, image manipulation is easier to detect. Our policies have always discouraged inappropriate manipulation. However, our approach to policing it was never to do more than to check a small proportion of accepted papers”.[12]

After the news about Nature’s oversight came out, the images in the STAP papers were subjected to the image analysis that EMBO Press uses. EMBO Press, a different publication company from Nature Publishing Company, has a thorough image evaluation and subjects all of their submissions to an image review. They found the spliced images, but said that splicing two images together is easier to detect. The duplications are harder [2]. Image analysis is one of several pre-publication precautions that could have been taken to ensure the validity of the results, including independent review of the experimental results and better oversight from RIKEN. For example, no one at RIKEN or at Harvard bothered to look at Obokata’s lab notebook, which was described as being disturbingly disorganized.

In an interview for the Knoepfler Lab’s Stem Cell Blog, a Nature representative said that “Nature Publishing Group utilises tools to do randomised spot check analysis of images but we currently do not have the resources to undertake detailed image analysis on all our papers.”[1]

Science as well as Retraction Watch reported on some of the comments made by the peer reviewers from the two other journals that rejected the STAP stem cell papers, Cell and Science. Science also reported that according to an email correspondence between the Nature editors and Dr. Obokata, the Nature editor initially rejected the papers, but was willing to look at a revised manuscript that addressed their concerns.[13]Nature did not comment on what changes the authors made to the manuscripts that were published in January, but the peer review commentary from the Science, Cell, and Nature reviewers all remark on the problems that appeared in the retracted papers. Retraction Watch provided the detailed cover letter from Science including the reviewer’s comments, here. Importantly, certain reviewer comments, such as problems with the images, were apparently not addressed by the authors in subsequent paper submissions to Nature. In other words, the lead author would have received these comments, and rather than addressing them, must have ignored them and submitted the papers to Nature.[14]

In a broader sense, we need to consider why we see such egregious cases of fraud and misconduct in the area of stem cell research. The STAP stem cell fiasco is not the first time that groundbreaking stem cell research has been riddled with discrepancies and misconduct.

It may be the case that fraud, plagiarism, and misconduct in peer reviewed scientific papers are common occurrences in any field, and cases involving stem cells just happen to make the news while others are either uninteresting or are left undetected.[15] Image discrepancies are more common, but are not necessarily due to misconduct. The reviewers at EBSCO Press find that 1% of their paper submissions have problems with the images. Most of these are not cases of fraud, but are usually cases of combining two images into one to present cleaner data. Others have criticized the “publish-or-perish” peer review model saying that it is fundamentally flawed, and that cases of misconduct are just symptoms to a larger problem.

Another possibility is that this is specific to stem cell research. Stem cell research is currently a high-profile area of research, which means that there are more people working in this field competing for the same pool of grant money. Many are also competing to be the first to find the next Nobel Prize-worthy breakthrough. Scientific research is an expensive endeavor, and higher-stakes research means greater pressure to publish positive results. It is unfortunately all too common that scientists over-promise in hopes of obtaining the necessary funds to do basic research.